Isoindolin-1-one derivatives

ABSTRACT

Isoindolin-1-one derivatives substituted on the nitrogen atom in the 2-position by an unsubstituted or substituted phenyl radical or a heterocyclic radical having aromatic characteristics, substituted in the 3-position by a 3-amino(or substituted amino)-2-hydroxy-propoxy group, and optionally substituted in the 5-and/or 6-positions by one or two alkoxy radicals or optionally substituted in the 5- and 6-positions by a methylenedioxy radical, possess pharmacodynamic properties, and are especially useful as anti-arrhythmic agents.

This is a division of application Ser. No. 341,307, filed Mar. 14, 1973now U.S. Pat. No. 3,898,232.

This invention relates to new therapeutically useful isoindolinederivatives, processes for their preparation and pharmaceuticalcompositions containing them.

The new isoindoline derivatives of the present invention are those ofthe general formula: ##SPC1##

[wherein Ar represent a phenyl radical or a heterocyclic radical havingaromatic characteristics, for example pyridyl or pyridazinyl, optionallycarrying one or two substituents, which -- in the latter case -- may beidentical or different, selected from halogen (e.g. chlorine) atoms,alkyl radicals containing 1 to 4 carbon atoms (e.g. methyl), alkoxyradicals containing 1 to 4 carbon atoms (e.g. methoxy), cyano and nitroradicals and the trifluoromethyl group, the symbols X and Y, which mayhave the same or different significances, each represent a hydrogen atomor an alkoxy radical containing 1 to 4 carbon atoms (preferablymethoxy), or X and Y together form a methylenedioxy radical, and thesymbols R₁ and R₂, which may have the same or different significances,each represent a hydrogen atom or an alkyl radical containing 1 to 4carbon atoms, or R₁ and R₂ together with the nitrogen atom to which theyare attached represent a mononuclear 5- or 6-membered heterocyclicradical, which may include a further hetero atom selected from oxygen,sulphur and nitrogen, and which may optionally carry as substituent analkyl radical containing 1 to 4 carbon atoms, for example piperidino,morpholino, or piperazin-1-yl optionally carrying on the 4-positionnitrogen atom an alkyl radical containing 1 to 4 carbon atoms(preferably methyl)], and acid addition salts thereof. It is to beunderstood that the aforementioned alkyl and alkoxy groups may havestraight-or branched-carbon chains.

According to a feature of the invention, the isoindoline derivatives ofgeneral formula I are prepared by the process which comprises reactingan amine of the general formula: ##STR1## (wherein R₁ and R₂ are ashereinbefore defined) with an isoindoline derivative of the generalformula: ##SPC2##

Wherein Ar, X and Y are as hereinbefore defined.The reaction isgenerally carried out by heating the isoindoline derivative of generalformula III with the amine of general formula II at the boiling point ofthe reaction mixture or under pressure in an autoclave. The reaction canalso be carried out by heating the reactants in an organic solvent, forexample benzene or toluene.

The isoindoline derivatives of general formula III can be obtained byreacting epichlorohydrin with an alkali metal salts, optionally preparedin situ, of an isoindoline derivative of the general formula: ##SPC3##

wherin Ar, X and Y are as hereinbefore defined. The reaction isgenerally carried out in an anhydrous organic solvent, for exampledimethylformamide, at a temperature below 60° C.

The compounds of general formula IV can be obtained by reducing aphthalimide of the general formula: ##SPC4##

(wherein Ar, X and Y are as hereinbefore defined) by methods known perse for reducing one of the carbonyl groups of phthalimide to a >CHOHgroup. The reduction is generally carried out by means of magnesium in amixture of methanol and a saturated solution of ammonium chloride or bymeans of an alkali metal borohydride in an aqueous or aqueous-alcoholicmedium.

When the phthalimido radical is substituted asymmetrically, the partialreduction of a compound of general formula V can lead to isomericproducts which can be separated by application of physico-chemicalmethods such as fractional crystallisation or chromatography.

The compounds of general formula V can be obtained by reacting an amineof the general formula:

    Ar -- NH.sub.2                                             VI

(wherein Ar is as hereinbefore defined) with an o-phthalic acidanhydride of the general formula: ##SPC5##

wherein X and Y are as hereinbefore defined.

According to another feature of the invention, the isoindolinederivatives of general formula X are prepared by the process whichcomprises reacting an epoxypropane of the general formula: ##STR2##(wherein R₁ and R₂ are as hereinbefore defined) with an alkali metalderivative, optionally prepared in situ, of an isoindoline derivative ofgeneral formula IV, wherein Ar, X and Y are as hereinbefore defined. Thereaction is generally carried out in an anhydrous organic solvent, forexample dimethylformamide, at a temperature below 30° C.

The epoxypropanes of general formula VIII can be obtained by reacting anamine of general formula II with epichlorohydrin.

The isoindoline derivatives of general formula I obtained by theaforementioned processes can be purified by physical methods such asdistillation, crystallisation or chromatography, or by chemical methodssuch as formation of salts, crystallisation of the salts anddecomposition of them in an alkaline medium. In carrying out the saidchemical methods the nature of the anion of the salt is immaterial, theonly requirement being that the salt must be well defined and readilycrystallisable.

The isoindoline derivatives of general formula I may be converted bymethods known per se into acid addition salts. The acid addition saltscan be obtained by the action of acids on the new compounds inappropriate solvents. As organic solvents there may be used alcohols,ketones, ethers, or chlorinated hydrocarbons. The salt which is formed,is precipitated, if necessary after concentration of the solution, andis isolated by filtration or decantation.

By the term "methods known per se" as used in this specification ismeant methods heretofore used or described in the chemical literature.

The isoindoline derivatives of the invention and their addition saltspossess valuable pharmacodynamic properties; they are very active asanti-arrhythmic agents. In vitro, at concentrations of between 1 and 10mg/liter, they have proved to be active in an investigation of theprolongation of the refractory period of auricles isolated from rabbits[G. S. Dawes, Brit. J. Pharmacol., 1, 90 (1946)]. In vivo, they haveproved to be active in rabbits against cardiographic anomalies caused byaconitine and in dogs against ventricular tachyarrhythmia caused byouabain [B. R. Lucchesi et al, J. Pharmacol., 132, 372 (1961) and Ann.N.Y. Acad. Sc., 139, art. 3, 940 (1967)] at doses between 0.1 and 10mg/kg animal body weight when administered intravenously.

Preferred isoindoline derivatives of the invention are those of generalformula I wherein the symbol Ar represents a phenyl, pyridyl (e.g.pyrid-2-yl) or pyridazinyl (e.g. pyridazin-3-yl) radical optionallysubstituted by a halogen (preferably chlorine) atom, an alkyl or alkoxyradical containing 1 to 4 carbon atoms (preferably methyl or methoxy) ora trifluoromethyl group, X and Y both represent hydrogen atoms or bothrepresent methoxy groups, R₁ represents an alkyl radical containing 1 to4 carbon atoms (preferably isopropyl or t.-butyl) and R₂ represents ahydrogen atom, or the grouping --NR₁ R₂ represents a piperazin-1-ylradical optionally carrying in the 4-position an alkyl radicalcontaining 1 to 4 carbon atoms (preferably methyl). Of outstandingimportance are those compounds wherein Ar represents a phenyl radical, Xand Y both represent hydrogen atoms, R₁ represents an alkyl radicalcontaining 1 to 4 carbon atoms (preferably isopropyl or t.-butyl), andR₂ represents a hydrogen atom, and especially3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-isoindolin-1-one and3-(2-hydroxy-3-t.-butylamino-propoxy)-2-phenyl-isoindolin-1-one.

For therapeutic purposes, the isoindoline derivatives of general formulaI may be employed as such or in the form of non-toxic acid additionsalts, i.e. salts containing anions which are relatively innocuous tothe animal organism in therapeutic doses of the salts (such ashydrochlorides, sulphates, nitrates, phosphates, acetates, propionates,succinates, benzoates, fumarates, maleates, tartrates,theophyllin-acetates, salicylates, phenolphthalinates andmethylene-bis-β-hydroxynaphthoates) so that the beneficial physiologicalproperties inherent in the bases are not vitiated by side effectsascribable to the anion.

The following non-limitative Examples illustrate the invention.

EXAMPLE 1

A solution of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (19.7 g.)in isopropylamine (50 cc.) is heated under reflux for 26 hours. Aftercooling the reaction mixture, di-isopropyl ether (100 cc.) is added andthe product which crystallises is filtered off and then washed withdi-isopropyl ether (50 cc.). After drying, a product (18.2 g.), meltingat 98° C., is obtained. On recrystallisation from acetonitrile (70 cc.),3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-isoindolin-1-one (14.1g.), melting at 98° C., is obtained.

3-(2,3-Epoxypropoxy)-2-phenyl-isoindolin-1-one employed as a startingmaterial can be prepared by adding a solution of3-hydroxy-2-phenyl-isoindolin-1-one (67.5 g.) in anhydrousdimethylformamide (180 cc.) to a suspension of sodium hydride (50%dispersion in mineral oil) (15.8 g.) in anhydrous dimethyl-formamide(250 cc.), whilst keeping the temperature at about 30° C. When theevolution of gas has ceased, epichlorohydrin (55.5 g.) is added and thetemperature is allowed to rise gradually to about 50° C. The reactionmixture is stirred for a further 5 hours, whilst allowing it to returnto a temperature of about 20° C., and is then poured into water (1,500cc.). The insoluble yellow oil is extracted three times with methylenechloride (total 800 cc.). The solution obtained is washed five timeswith water (total 1,250 cc.), dried over sodium sulphate and thenconcentrated to dryness under reduced pressure. A brown oil (85 g.) isobtained and is dissolved in a mixture of methylene chloride andcyclohexane (1/1 by volume; 500 cc.). The solution obtained is filteredthrough silica gel (800 g.) contained in a column 6.5 cm. in diameter.Elution is then carried out with a mixture of methylene chloride andcyclohexane (1/1 by volume; 2,500 cc.) and then with a mixture ofmethylene chloride and cyclohexane (3/1 by volume; 1,000 cc.). Theseeluates are discarded. Elution is then carried out with a mixture ofmethylene chloride and cyclohexane (3/1 by volume; 10,000 cc.) and thenwith pure methylene chloride (4,000 cc.). These eluates are combined andconcentrated to dryness under reduced pressure. The residue obtained istreated with diethyl ether (150 cc.) and the insoluble product isfiltered off and then washed with diethyl ether (50 cc.). After drying,3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (44.4 g.), melting at 76°C., is obtained.

3-Hydroxy-2-phenyl-isoindolin-1-one can be prepared according to themethod described by A. Dunet and A. Willemart, Bull, Soc. Chim. P. 1,045(1948).

EXAMPLE 2

A solution of 3-hydroxy-2-phenyl-isoindolin-1-one (6.75 g.) in anhydrousdimethylformamide (20 cc.) is added to a suspension of sodium hydride(50% dispersion in mineral oil) (1.48 g.) in anhydrous dimethylformamide(20 cc.). When the evolution of gas has ceased,2,3-epoxy-1-isopropylamino-propane (3.8 g.) is added whilst keeping thetemperature at about 5° C. After the end of the addition, stirring iscontinued for a further 24 hours at a temperature of about 20° C. andthen the reaction mixture is poured into ice-water (250 cc.). Theinsoluble oily product is extracted with methylene chloride (3 × 100cc.). The solution obtained is dried over sodium sulphate and thenconcentrated to dryness under reduced pressure. The oily residue istaken up in diethyl ether (50 cc.) and the insoluble product is filteredoff and then washed with diethyl ether (30 cc.). The filtrate is thenextracted with 0.5N hydrochloric acid (60 cc.). The acid solutionobtained is washed with diethyl ether (20 cc.) and then renderedalkaline by the addition of 1N sodium hydroxide solution (30 cc.). Theinsoluble oily product is extracted with diethyl ether (2 × 50 cc.) andthe solution obtained is dried over sodium sulphate and thenconcentrated to dryness under reduced pressure. The oily productobtained is dissolved in a mixture of diethyl ether and di-isopropylether (1/1 by volume; 20 cc.), and the product which crystallises isfiltered off and then washed with a mixture of diethyl ether anddi-isopropyl ether (1/1 by volume; 5 cc.). After drying,3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-isoindolin-1-one (1.35g.), melting at 92° C., is obtained.

2,3-Epoxy-1-isopropylamino-propane employed as a starting material canbe prepared by slowly adding isopropylamine (34.8 g.) to a mixture ofepichlorohydrin (55.6 g.) and water (2 cc.), at a temperature of about30° C. The reaction mixture is stirred for a further 2 hours at atemperature of about 20° C. and then a solution of sodium hydroxide (28g.) in water (50 cc.) is added slowly, whilst maintaining thistemperature. The reaction mixture is stirred for a further hour at atemperature of about 20° C. and is then poured into water (140 cc.). Theinsoluble oily product is extracted with diethyl ether (3 × 50 cc.). Thesolution obtained is washed with water (2 × 20 cc.), dried withpotassium hydroxide pellets (13 g.) and then concentrated to dryness.After distilling the residue under reduced pressure,2,3-epoxy-1-isopropylamino-propane (5.2 g.), b.p. 62° C./32 mm.Hg, isobtained.

EXAMPLE 3

A solution of 2-(4-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one(15 g.) and isopropyl-amine (75 cc.) in anhydrous toluene (250 cc.) isheated under reflux for 5 days. The reaction mixture is then evaporatedto dryness under reduced pressure and the residue obtained isrecrystallised from ethyl acetate (60 cc.). After drying,2-(4-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one(13 g.), melting at 107° C., is obtained.

2-(4-Chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one employed as astarting material can be prepared by adding a solution of2-(4-chlorophenyl)-3-hydroxy-isoindolin-1-one (24 g.) in anhydrousdimethylformamdie (180 cc.) to a suspension of sodium hydride (50%dispersion in mineral oil) (4.85 g.) in anhydrous dimethylformamide (100cc.). When the evolution of gas has ceased, epichlorohydrin (25.5 g.) isadded and the mixture is stirred for 20 hours at a temperature of about20° C. The reaction mixture is then poured into ice-water (1,750 cc.)and the oily product which separates out is extracted with methylenechloride (4 × 200 cc.). The solution obtained is dried over sodiumsulphate and then evaporated to dryness under reduced pressure. The oilthus obtained is dissolved in isopropanol (35 cc.). The product whichcrystallises is filtered off and then washed with isopropanol (14 cc.)and di-isopropyl ether (50 cc.). After drying2-(4-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (17.4 g.),melting at 90°-92° C., is obtained.

2-(4-Chlorophenyl)-3-hydroxy-isoindolin-1-one can be prepared by addinga saturated aqueous solution of ammonium chloride (150 cc.) to asuspension of 2-(4-chlorophenyl)phthalimide (25.75 g.) and magnesiumturnings (8.8 g.) in methanol (1,000 cc.). After heating the reactionmixture under reflux for 2 hours and then stirring at 20° C. for 20hours, it is again heated to the boiling point, decolourizing charcoal(10 g.) is then added and the mixture is filtered whilst hot. Afterevaporating the methanol under reduced pressure, water (500 cc.) isadded to the residue. A product crystallises and is filtered off andwashed with water (200 cc.). After drying, a product (21.8 g.), meltingat 200° C., is obtained. On recrystallisation from ethanol (350 cc.),2-(4-chlorophenyl)-3-hydroxy-isoindolin-1-one (14.6 g.), melting at 200°C., is obtained.

2-(4-Chlorophenyl)-phthalimide can be prepared according to the methoddescribed by G. Pagani et al, I1 Farmaco, Ed. Sci., 23, [5], 448 (1968).

EXAMPLE 4

A solution of 2-(3-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one(12 g.) and isopropyl-amine (120 cc.) in anhydrous toluene (200 cc.) isheated under reflux for 5 days. The reaction mixture is then evaporatedto dryness under reduced pressure and the residue obtained isrecrystallised from ethyl acetate (65 cc.). After drying,2-(3-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one(11.6 g.), melting at 128° C., is obtained.

2-(3-Chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one employed as astarting material can be prepared by adding a solution of2-(3-chlorophenyl)-3-hydroxy-isoindolin-1-one (19.5 g.) in anhydrousdimethylformamide (125 cc.) to a suspension of sodium hydride (50%dispersion in mineral oil) (3.96 g.) in anhydrous dimethylformamide (150cc.). When the evolution of gas has ceased, epichlorohydrin (21 g.) isadded and the mixture is stirred for 20 hours at a temperature of about20° C. The reaction mixture is then poured into ice-water (1,500 cc.)and the oily product which separates out is extracted with methylenechloride (3 × 400 cc.). The solution obtained is dried over sodiumsulphate and then evaporated to dryness under reduced pressure. The oilthus obtained is taken up in isopropanol (40 cc.). The product whichcrystallises is filtered off and then washed with isopropanol (10 cc.)and di-isopropyl ether (40 cc.). After drying,2-(3-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (12.4 g.),melting at 123°-125° C., is obtained.

2-(3-Chlorophenyl)-3-hydroxy-isoindolin-1-one can be prepared by addinga saturated aqueous solution of ammonium chloride (150 cc.) to asuspension of 2-(3-chlorophenyl)phthalimide (25.75 g.) and magnesiumturnings (8.8 g.) in methanol (1,000 cc.). After heating under refluxfor 2 hours followed by stirring at 20° C. for 20 hours, decolourizingcharcoal (10 g.) is added, the mixture is filtered and the methanol isthen distilled under reduced pressure. Water (500 cc.) is then added tothe residue. The product which crystallises is filtered off and thenwashed with water (200 cc.). After drying, a product (18.9 g.), meltingat 170° C., is obtained. On recrystallisation from ethanol (200 cc.),2-(3-chlorophenyl)-3-hydroxy-isoindolin-1-one (11.5 g.), melting at 172°C., is obtained.

2-(3-Chlorophenyl)phthalimide can be prepared according to the methoddescribed by G. Pagani et al, I1 Farmaco, Ed. Sci., 23, [5], 448 (1968).

EXAMPLE 5

Following the procedure of Example 3 but starting with3-(2,3-epoxypropoxy)-2-(3-methoxyphenyl)-isoindolin-1-one (28.5 g.) andisopropylamine (142 cc.),3-(2-hydroxy-3-isopropylamino-propoxy)-2-(3-methoxyphenyl)-isoindolin-1-one(15.7 g.), melting at 110° C., is obtained after recrystallisation fromethyl acetate.

3-(2,3-Epoxypropoxy)-2-(3-methoxyphenyl)-isoindolin-1-one, in the formof a yellow oil, can be prepared following the procedure described inExample 1 for the preparation of the similar starting material from3-hydroxy-2-(3-methoxyphenyl)-isoindolin-1-one (20.8 g.), sodium hydride(50% dispersion in mineral oil) (4.3 g.) and epichlorohydrin (22.6 g.).

3-Hydroxy-2-(3-methoxyphenyl)isoindolin-1-one can be prepared accordingto the method described in the specification of Belgian Patent No.776,682, granted to Rhone-Poulenc S.A. on an application filed Dec. 14,1971.

EXAMPLE 6

A mixture of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (2.8 g.) andt.-butylamine (8.4 cc.) is heated in an autoclave at 100° C. for 20hours. (85 cc.) and the insoluble product is extracted with methylenechloride (75 cc.) The organic solution is washed with water (2 × 25 cc.)and then with 0.3N hydrochloric acid (2 × 30 cc.). The acid solutionobtained is rendered alkaline by addition of 1N sodium hydroxidesolution (20 cc.). The insoluble oily product is extracted withmethylene chloride (2 × 35 cc.), and then the organic solution obtainedis dried over sodium sulphate and concentrated to dryness under reducedpressure. After two successive recrystallisations of the resultingresidue from acetone,3-(2-hydroxy-3-t.-butylamino-propoxy)-2-phenyl-isoindolin-1-one (1.6g.), melting at 125°-130° C., is obtained.

EXAMPLE 7

Following the procedure of Example 3 but starting with3-(2,3-epoxypropoxy)-2-(3-trifluoromethyl-phenyl)-isoindolin-1-one (7.5g.) and isopropylamine (37.5 cc.),3-(2-hydroxy-3-isopropylamino-propoxy)-2-(3-trifluoromethylphenyl)-isoindolin-1-one(5.8 g.), melting at 125° C., is obtained after recrystallisation fromacetonitrile.

3-(2,3-Epoxypropoxy)-2-(3-trifluoromethyl-phenyl)-isoindolin-1-one, inthe form of a yellow oil, can be prepared following the proceduredescribed in Example 1 for the preparation of the similar startingmaterial from 3-hydroxy-2-(3-trifluoromethylphenyl)-isoindolin-1-one (16g.), sodium hydride (50% dispersion in mineral oil) (2.88 g.) andepichlorohydrin (15 g.).

3-Hydroxy-2-(3-trifluoromethylphenyl)-iso-indolin-1-one can be preparedby adding a solution of potassium borohydride (11.3 g.) in water (93cc.) and 1N sodium hydroxide solution (11.3 cc.) to a suspension ofN-(3-trifluoromethylphenyl)-phthalimide (80.9 g.) in methanol (380 cc.),whilst keeping the temperature at about 20° C. The reaction mixture isthen stirred for 18 hours at a temperature of about 20° C. The insolubleproduct is filtered off and then washed with ethanol (50 cc.) andpetroleum ether (100 cc.). After drying,3-hydroxy-2-(3-trifluoromethylphenyl)-isoindolin-1-one (63.9 g.),melting at 202° C., is obtained.

N-(3-Trifluoromethylphenyl)-phthalimide can be prepared according to themethod described by G. Pagani et al, I1 Farmaco, Ed. Sci. 23 [5], 448(1968).

EXAMPLE 8

A solution of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (8.4 g.)and 1-methylpiperazine (3.6 g.) in anhydrous toluene (84 cc.) is heatedunder reflux for 3 days. After cooling, the reaction mixture is washedwith water (2 × 50 cc.) and then the organic solution is extracted with1N hydrochloric acid (55 cc.) and water (3 × 20 cc.). The aqueous andacid solutions are combined and are rendered alkaline by addition of 1Nsodium hydroxide solution (55 cc.). The oil which separates out isextracted with methylene chloride (150 cc.) and then the organicsolution obtained is dried over sodium sulphate and concentrated todryness under reduced pressure. The residual oil is dissolved in ethanol(20 cc.) and the resulting solution is added to a hot solution offumaric acid (5.85 g.) in ethanol (80 cc.). The product whichcrystallises on cooling is filtered off and then washed with ethanol (30cc.) and di-isopropyl ether (40 cc.). After drying,3-[2-hydroxy-3-(4-methylpiperazin-1-yl)-propoxy]-2-phenyl-isoindolin-1-oneacid difumarate (14.5 g.), melting at 194° C., is obtained.

EXAMPLE 9

A solution of2-(5-chloropyrid-2-yl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (11.4 g.)in isopropylamine (57 cc.) is heated under reflux for 26 hours. Aftercooling, the reaction mixture is concentrated to dryness under reducedpressure. On recrystallisation of the resulting residue from ethylacetate (20 cc.),2-(5-chloropyrid-2-yl)-3-(2-hydroxy-3-isopropylamino-propoxy)-iso-indolin-1-one(10.6 g.), melting at 107° C., is obtained.

2-(5-Chloropyrid-2-yl)-3-(2,3-epoxypropoxy)-isoindolin-1-one, melting at123° C., can be prepared from2-(5-chloropyrid-2-yl)-3-hydroxy-isoindolin-1-one (20.8 g.), sodiumhydride (50% dispersion in mineral oil) (4.2 g.) and epichlorohydrin(14.8 g.).

2-(5-Chloropyrid-2-yl)-3-hydroxy-isoindolin-1-one can be preparedaccording to the method described in the specification of Belgian PatentNo. 771,493 granted to Rhone-Poulenc S.A. on an application filed Aug.14, 1971.

EXAMPLE 10

A solution of3-(2,3-epoxypropoxy)-2-(6-methylpyridazin-3-yl)-isoindolin-1-one (17.4g.) in isopropylamine (87 cc.) is heated under reflux for 26 hours. Thereaction mixture is then concentrated to dryness under reduced pressure.The residual oil is dissolved in ethyl acetate (400 cc.) and thesolution obtained is filtered through silica gel (400 g.) contained in acolumn 4 cm. in diameter. Elution is then carried out successively withpure ethyl acetate (1,200 cc.), a mixture of ethyl acetate and methanol(95/5 by volume; 3,200 cc.), a mixture of ethyl acetate and methanol(90/10 by volume; 1,600 cc.) and a mixture of ethyl acetate and methanol(80/20 by volume; 1,200 cc.). All these eluates are discarded. Elutionis then carried out with a mixture of ethyl acetate and methanol (80/20by volume; 2,800 cc.) and then with a mixture of ethyl acetate andmethanol (50/50 by volume; 1,600 cc.). After concentrating these eluatesto dryness and recrystallising the residue from a mixture ofdi-isopropyl ether and acetonitrile (85/15 by volume),3-(2-hydroxy-3-isopropylamino-propoxy)-2-(6-methylpyridazin-3-yl)-isoindolin-1-one (4 g.), melting at 90° C., is obtained.

3-(2,3-Epoxypropoxy)-2-(6-methylpyridazin-3-yl)-isoindolin-1-one,melting at 110° C., can be prepared by the procedure described inExample 3 for the preparation of the similar starting material from3-hydroxy-2-(6-methylpyridazin-3-yl)-isoindolin-1-one (18 g.), sodiumhydride (50% dispersion in mineral oil) 3.95 g.) and epichlorohydrin (21g.).

2-(6-Methylpyridazin-3-yl)-3-hydroxy-isoindolin-1-one can be prepared byadding a solution of potassium borohydride (3.64 g.) in water (29 cc.)and 1N sodium hydroxide solution (3.8 cc.) to a suspension of3-methyl-6-phthalimido-pyridazine (21 g.) in methanol (105 cc.), whilststirring and keeping the temperature at about 15° C. After 2 hours at20° C., the insoluble product is filtered off and then washed withmethanol (60 cc.). After drying,2-(6-methylpyridazin-3-yl)-3-hydroxy-isoindolin-1-one (18.4 g.), meltingat 232° C., is obtained.

3-Methyl-6-phthalimido-pyridazine can be prepared by heating a mixtureof phthalic anhydride (14.8 g.) and 3-amino-6-methyl-pyridazine (10.9g.) in diphenyl ether (74 cc.), for 20 minutes at a temperature of about190° C. The reaction mixture is then allowed to return to 45° C. anddi-isopropyl ether (25 cc.) is added. The product which crystallises isfiltered off and then washed with di-isopropyl ether (30 cc.). Afterdrying, 3-methyl-6-phthalimido-pyridazine (21.5 g.), melting at 214° C.,is obtained

3-Amino-6-methyl-pyridazine can be prepared according to the methoddescribed by W. G. Overend and L. F. Wiggins, J. Chem. Soc., p. 239(1947).

EXAMPLE 11

A solution of3-(2,3-epoxypropoxy)-5,6-dimethoxy-2-phenyl-isoindolin-1-one (4.7 g.)and isopropylamine (27.6 cc.) in toluene (15 cc.) is heated in anautoclave at 100° C. for 18 hours. After cooling, the reaction mixtureis concentrated to dryness under reduced pressure. After recrystallisingthe resulting residue from a mixture of ethyl acetate anddi-isopropylether (50/50 by volume; 40 cc.),3-(2-hydroxy-3-isopropyl-amino-propoxy)-5,6-dimethoxy-2-phenyl-isoindolin-1-one(3 g.), melting at 110° C., is obtained.

3-(2,3-Epoxypropoxy)-5,6-dimethoxy-2-phenyl-isoindolin-1-one, melting at142° C., can be prepared by the procedure described in Example 4 for thepreparation of the similar starting material from3-hydroxy-5,6-dimethoxy-2-phenyl-isoindolin-1-one (4.5 g.), sodiumhydride (50% dispersion in mineral oil) (0.85 g.) and epichlorohydrin(4.4 g.).

3-Hydroxy-5,6-dimethoxy-2-phenyl-isoindolin-1-one, melting at 205° C.,can be prepared as described in Example 3 for the preparation of2-(4-chlorophenyl)-3-hydroxy-isoindolin-1-one, but starting with4,5-dimethoxy-2-phenyl-phthalimide (5.7 g.) and magnesium turnings (1.8g.) in a mixture of methanol and a saturated solution of ammoniumchloride.

4,5-Dimethoxy-2-phenyl-phthalimide can be prepared by heating a solutionof 4,5-dimethoxy-phthalic anhydride (15 g.) and aniline (6.7 g.) inacetic acid (150 cc), under reflux for 1 hour. The product whichcrystallises on cooling is filtered off and then washed withdi-isopropyl ether (50 cc.). After drying4,5-dimethoxy-2-phenyl-phthalimide (18.8 g.), melting at 245° C., isobtained.

4,5-Dimethoxy-phthalic anhydride can be prepared according to the methoddescribed by G. A. Edwards et al, J. Chem. Soc., 195 (1925).

The present invention includes within its scope pharmaceuticalcompositions comprising, as active ingredient, at least one isoindolinederivative of general formula I, or a non-toxic acid addition saltthereof, in association with a pharmaceutical carrier or coating. Theinvention includes especially such preparations made up for oral,parenteral or rectal administration.

Solid compositions for oral administration include tablets, pills,powders and granules. In such solid compositions the active compound isadmixed with at least one inert diluent such as sucrose, lactose orstarch. The compositions may also comprise, as is normal practice,additional substances other than inert diluents, e.g. lubricatingagents, such as magnesium stearate. Liquid compositions for oraladministration include pharmaceutically-acceptable emulsions, solutions,suspensions, syrups and elixirs containing inert diluents commonly usedin the art, such as water or liquid paraffin. Besides inert diluentssuch compositions may also comprise adjuvants, such as wetting,emulsifying and suspending agents, and sweetening, flavouring andaromatizing agents. The compositions according to the invention, fororal administration, also include capsules of absorbable material suchas gelatin containing the active substance with or without the additionof diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils such as olive oil, andinjectable organic esters such as ethyl oleate. These compositions mayalso contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporation in thecompositions of sterilizing agents, by irradiation, or by heating. Theymay also be manufactured in the form of sterile solid compositions,which can be dissolved in sterile water or some other sterile injectablemedium immediately before use.

Compositions for rectal administration are suppositories which contain,in addition to the active substance, excipients such as cacao butter ora suitable wax base.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. The dosage depends on thedesired therapeutic effect, on the route of administration and on theduration of the treatment. In human therapy the compositions whenadministered orally to an adult should generally give does between 50mg. and 1000 mg. of active substance per day. In general the physicianwill decide the posology considered appropriate, taking into account theage and weight and other factors intrinsic to the patient being treated.

The following Example illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 12

Tablets containing 25 mg. of active product and having the followingcomposition are prepared in accordance with the usual technique:

    ______________________________________                                        3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-                              isoindolin-1-one            0.025 g.                                          starch                      0.100 g.                                          precipitated silica         0.022 g.                                          magnesium stearate          0.003 g.                                          ______________________________________                                    

We claim:
 1. An isoindoline of the formula: ##SPC6##wherein Ar ispyridyl, unsubstituted or substituted by one or two substituentsselected from halogen, alkyl of 1 through 4 carbon atoms, alkoxy of 1through 4 carbon atoms, cyano, nitro and trifluoromethyl, X and Y whentaken singly represent hydrogen or alkoxy of 1 through 4 carbon atoms,or X and Y when taken together represent methylenedioxy, and R₁ and R₂represent hydrogen or alkyl of 1 through 4 carbon atoms, or a non-toxicpharmaceutically acceptable acid addition salts thereof.
 2. Anisoindoline according to claim 1 wherein Ar is pyridyl unsubstituted orsubstituted by halogen, alkyl of 1 through 4 carbon atoms, alkoxy of 1through 4 carbon atoms or trifluoromethyl, X and Y both representhydrogen or both represent methoxy, R₁ represents alkyl of 1 through 4carbon atoms and R₂ represents hydrogen, or a non-toxic pharmaceuticallyacceptable acid addition salt thereof.
 3. An isoindoline derivativeaccording to claim 1 wherein the substituent or substituents on theradical represented by the symbol Ar is, or are, selected from chlorine,methyl, methoxy and trifluoromethyl, or a non-toxic pharmaceuticallyacceptable acid addition salt thereof.
 4. An isoindoline derivativeaccording to claim 1 wherein R₁ represents isopropyl or t.-butyl and R₂represents hydrogen.
 5. The isoindoline derivative according to claim 1which is2-(5-chloropyrid-2-yl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-oneor a non-toxic pharmaceutically acceptable acid addition salt thereof.6. A pharmaceutical composition useful as an anti-arrhythmic whichcomprises, as active ingredient, an effective amount of an isoindolineof claim 1, or a non-toxic pharmaceutically acceptable acid additionsalt thereof, in association with a significant amount of apharmaceutically acceptable carrier.